Technical Field
The present invention primarily relates to a gel-forming system, more particularly an adhesive-forming system, for use in a method for removing urinary calculi and/or fragments thereof, more particularly kidney stones and/or fragments thereof, from the body, more particularly from the urinary tract. More particularly, the present invention relates to a gel-forming system, more particularly to an adhesive-forming system, consisting of or comprising a composition (A), comprising one or several cationically crosslinkable polymer(s), and a composition (B), comprising one or several crosslinking agent(s) for crosslinking the cationically crosslinkable polymer(s), so that upon contact of composition (A) with composition (B) in a region of the urinary tract, more particularly in the kidney, that contains urinary calculi and/or fragments thereof, more particularly kidney stones and/or fragments thereof, a crosslinked gel is formed that partly or fully surrounds the urinary calculi and/or fragments thereof, more particularly the kidney stones and/or fragments thereof.
Furthermore, the present invention relates to a gel-forming system, more particularly an adhesive-forming system, consisting of or comprising compositions (A) and (B) as described herein, as well as in addition comprising magnetizable particles for partly or fully surrounding urinary calculi and/or fragments thereof, more particularly kidney stones and/or fragments thereof, by forming a crosslinked gel upon contact of composition (A) with composition (B), wherein the crosslinked gel contains the magnetizable particles.
The present invention thus also relates to a crosslinked gel, more particularly an adhesive, for partly or fully surrounding urinary calculi and/or fragments thereof, more particularly kidney stones and/or fragments thereof, wherein the crosslinked gel contains magnetizable particles and is producible or produced by means of providing a composition (A) and (B) as described herein, as well as optionally a composition (C), wherein composition (A) and/or composition (B) and/or composition (C) comprise magnetizable particles, and contacting compositions (A) and (B) (as well as (C), if applicable) under conditions that enable crosslinking of the cationically crosslinkable polymer(s) so that a crosslinked gel is formed.
Description of the Related Art
Urinary calculi can be formed in the revulsive urinary tract. A urinary obstruction first leads to strong, labor-like pain (so called renal colic). If left untreated, urinary calculi can lead to serious health problems (loss of renal function, inflammation) and vitally endanger the patient (sepsis during infected urinary calculus-caused urinary transport disorder). From an epidemiological point of view, urinary calculus conditions are one of the most prevalent diseases afflicting mankind, whose incidence in Germany amounted to 1.45% in the year 2000, which in turn corresponds to 1,200,000 new cases per year. In Germany alone a total of ca. 750,000 cases of treatment can be expected per year. The number of treatments for removing calculi in Germany is estimated to be about 400,000 per year, about half thereof being treatments of recurring calculi. The numbers referred to can be extrapolated to a millionfold implementation of such treatments worldwide. With a sum of over 1.5 billion Euros, urinary calculus conditions represent a substantial cost factor for the German healthcare sector.
If the calculi do not exit the body by natural routes or if medicinal indications for immediate therapy exist, endoscopy (minimally invasive endoscopy techniques) represents the therapeutic “gold standard” besides the extracorporeal shock wave treatment (ESWT). In light of increasing evidence for worse results of ESWT, endoscopic methods are preferably used. It can be assumed that currently 60-70% of calculi patients are treated endoscopically. This tendency is increasing. With the help of endoscopic techniques, calculi are locally crushed and removed. To date, small residual fragments (<2 mm), that cannot be removed effectively during treatment, pose an unsolved problem. Remaining fragments of kidney stones act as “crystal seeds” from which new calculi are formed with a likelihood of 70%. This in turn leads again to medicinal problems and need for treatment.
About 30 million people in Europe are suffering from kidney stones (ca. 5% of the population), and the frequency of occurrence of urinary calculi conditions shows an increasing tendency in industrialized countries. The risk to be repeatedly affected by kidney stones after recovery is particularly high (ca. 60%). Medicinal complications that can arise in connection with kidney stones are loss of renal function and infectious complications all the way to sepsis. This results in a severe burden for the healthcare systems.
One option to specifically navigate the position and distribution of substances or objects in the body is the utilization of magnetic interactions. For this purpose, the target substances and target objects, respectively, have to be magnetized accordingly. Magnetic (nano)particles have already proven to be suitable in different biomedical applications, since they have high biocompatibility and can be modified with different functional groups. Thus, magnetic particles are used, for example, to transport active substances to a desired site of action in the body. Hence, therapeutic and diagnostic substances can be used efficiently and damages in healthy tissues caused by potential side effects can be minimized.
In this context, US 2007/0231393 describes a method in which magnetic drug carrier particles are positioned in the body by means of an external magnetic field.
US 2009/0136594 is concerned with a method to magnetize biological particles by contacting them with magnetic particles which are modified such that they are able to bind specifically to the biological particles. Kidney stones and fragments thereof can be magnetized as one possible application to remove them from the body by means of equipment that magnetically attracts such particles. In order to specifically bind calcium-based biominerals (such as, for example, kidney stones), the particles are modified with certain calcium-binding proteins or fragments thereof.
Larger calculi usually cannot be removed by means of a minimally invasive procedure and therefore have to be smashed into smaller fragments first and have to be dissolved completely or at least partly, respectively. A method for treatment of kidney stones through specific dissolution of the deposits by using quaternary ammonium salts is described, for example, in U.S. Pat. No. 5,244,913.
Another possibility for treating kidney stones without smashing them beforehand is specified in US 2006/0269512. Here, the natural peristalsis is used to press a polymer clot through a lumen and to thereby remove the calculus from the lumen. The polymer clot can be formed in situ through temperature or pH change or through ionic interactions.
Lithotripsy is a method where kidney stones are smashed by means of extracorporeal shock waves or endoscopically inserted laser or compressed air probes. Thereby, fragments of different sizes are formed which can be removed with the aid of grasping instruments or can be flushed out. One problem occurring during lithotripsy is that the fragments are able to spread or reach regions that are hard to access.
WO 2005/037062 relates to a method in which kidney stones are enclosed (not enclosed in) in a certain area with the aid of a polymer clot, whereby damages to the tissues through the formed fragments during smashing can be prevented to a large extent. According to WO 2005/037062, a gel-forming liquid, for example a thermosensitive polymer, is injected into the lumen on at least one side of the kidney stone, which forms a gel clot at body temperature. The polymer thereby usually does not get into contact with the kidney stone, but serves to increase the efficiency of the lithotripsy by preventing shifting of the kidney stone and by protecting the surrounding tissue from damage through fragmentation.
According to US 2008/0103481, a biocompatible polymer clot is used more particularly to prevent a backwards shift of kidney stones or fragments thereof during lithotripsy and thereby to minimize the damage to the surrounding tissues.
An approach to remove objects, such as for example blood clots, from the body using an adhesive is specified in US 2008/0065012. In the process, the adhesive is distributed on a surface and inserted into the body with the aid of a catheter. When is object is adhered to the surface, the catheter is removed and takes the object with it.
Adhesives based on biological macromolecules and more particularly gel-forming polymer systems are used increasingly in medical technology. Thereby, their high biocompatibility is one of their most important selection criteria.
Thermosensitive or ionically polymerizable polymers are used, for example, to stop the blood flow from injured blood vessels. WO 2008/103891 specifies a method in which the outflow of biological fluids from tissues or vessels can be controlled through in situ formation of a polymer clot.
WO 01/05443 relates to an adhesive protein foam and its use for surgical and therapeutic applications. The foam consists of a liquid protein matrix and a biocompatible gas and serves for covering and protecting, respectively, injured tissue or for connecting implanted tissue with biological tissue.
WO 02/18448 describes the pharmaceutical use of percarboxylated polysaccharides in the manufacture of biomaterials for surgical and biomedical applications. Such material are especially well suited for use in the body since they are recognized as being endogenous and do not trigger any immune rejection reaction. Therefore, they can be used as coatings for implants.
A method for encapsulation of renal tissue in spheres of biocompatible polymers is described in US 2009/0162411. The aim of such encapsulation is to maintain renal tissue implants, which can be injected into a patient who suffers from a renal function disorder in order to support renal function.
Calcium alginate as a biocompatible hydrogel polymer for closing skull openings after open brain surgery is disclosed in WO 2004/080343.
The suitability of polysaccharide-containing polymers for binding biologically active molecules or whole cells in the field of organ transplantation and of artificial tissue replacement is described in WO 1998/012228.
Alginates are also used as fillers for supporting skin and muscles in the medicinal and cosmetic field. In US 2011/0097367 applications are described in which monolithic alginate implants are formed in situ by means of injection of a pure, high molecular weight alginate solution into the tissue and spontaneous crosslinking Crosslinking takes place through Ca2+ ionic bridges without the need of having to add additional crosslinking agents. The described alginate implants are suitable for the treatment of wrinkles or different conditions in which the muscular structure is weakened.
In U.S. Pat. No. 6,663,594 B2, a method for immobilization of an object in the body, for example a kidney stone, is described, wherein a gel-forming liquid is injected into the body. Upon contact with the object, a gel is formed, which at least partly captures and immobilizes the object. The immobilization serves for being able to subsequently fragment the object without risking distribution of the fragments and for removing the object or fragments, respectively, from the body with an endoscopic tool. The gel thereby prevents the object or fragment, respectively, from shifting and not being able to be grasped with the tool. After removal of the object or fragments, respectively, the gel is dissolved or extracted with the aid of an endoscopic tool. A disadvantage of the method is that during smashing of the kidney stones the gel that is already set might be destroyed and thereby fragments can be released again or that discrete fragments might escape from the polymer. In addition, the described procedure is very time-consuming, since the calculi or fragments thereof have to be grasped and removed individually. Consequently, individual calculus fragments will remain behind with a relatively high likelihood.
More particularly, one problem of lithotripsy is the occurrence of medium sized calculus fragments (more particularly <2 mm), also called “gravel”, since these fragments can neither be grasped efficiently nor flushed. Residual fragments of this size slide through the mesh of the grasping instruments (grasping forceps or baskets) and render the extraction of gravel very time-consuming and with larger amounts of calculi practically unfeasible. To date, no technology has been successfully established to fully remove the medium size and small calculus fragments. Such kidney stone fragments remaining behind, however, in a large percentage of cases lead to the formation of new kidney stones, since the fragments serve as “crystal seeds”.
In order to ensure complete removal of fragments of any size, a new method has to be developed which is suited to ideally reliably capture all of the fragments. Thereby, the problems and difficulties (partly mentioned above) that are entailed in the methods known in the state of the art, shall preferably be avoided.